Heterocyclic compound and application thereof

ABSTRACT

wherein each symbol is as described in the specification, or a salt thereof, has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound, particularly,a heterocyclic compound having an orexin type 2 receptor agonistactivity.

BACKGROUND OF THE INVENTION

Orexin is a neuropeptide specifically produced in particular neuronslocated sparsely in the lateral hypothalamus and its surrounding area,and consists of two subtypes, orexin A and orexin B. Both orexin A andorexin B are endogenous ligands of the orexin receptors, which are Gprotein-coupled receptors mainly present in the brain, and two types ofsubtypes, type 1 and type 2, are known for the orexin receptors(non-patent document 1).

Since orexin-producing neurons (orexin neurons) are localized in thevicinity of the feeding center, and intraventricular administration oforexin peptide results in an increase in food intake, orexin initiallyattracted attention as a neuropeptide having a feeding behavioralregulation. Thereafter, however, it was reported that the cause of dognarcolepsy is genetic variation of orexin type 2 receptor (non-patentdocument 2), and the role of orexin in controlling sleep and wakefulnesshas been also attracted.

From the studies using a transgenic mouse having denatured orexinneurons and a double transgenic mouse obtained by crossing this mousewith orexin overexpressing transgenic mouse, it was clarified thatnarcolepsy-like symptoms that appear by degeneration of orexin neuronsdisappear due to sustained expression of orexin. Similarly, when orexinpeptide was intraventricularly administered to a transgenic mouse havingdenatured orexin neuron, improvement of narcolepsy-like symptoms wasalso observed (non-patent document 3). Studies of orexin type 2 receptorknockout mice have suggested that orexin type 2 receptor is importantfor maintaining arousal (non-patent document 4, non-patent document 5).Such background suggests that orexin type 2 receptor agonists becometherapeutic drugs for narcolepsy or therapeutic drugs for other sleepdisorders exhibiting excessive sleepiness (non-patent document 6).

In addition, it is suggested that a peptidic agonist that selectivelyacts on the orexin type 2 receptor improves obesity due to high fat dietload in mice (non-patent document 7).

In addition, it is suggested that intraventricular administration oforexin peptide shortens the systemic anesthetic time of rat (non-patentdocument 8).

In addition, it is suggested that patients with sleep apnea syndromeshow low orexin A concentration levels in plasma (non-patent document9).

In addition, it is suggested that intraventricular administration oforexin peptide improves memory retention of senescence-accelerated modelmouse (SAMP8) with cognitive dysfunction (non-patent document 10).

In addition, it is suggested that Orexin type 2 receptor agonist will bea therapeutic drug for cardiac failure (patent document 1, non-patentdocument 11).

In addition, it is suggested that the daytime sleepiness of Parkinson'sdisease patients is caused by orexin nerve fallout (non-patent document12).

In addition, it is suggested that orexin regulates bone formation andbone loss, and orexin type 2 receptor agonist will be a therapeutic drugfor diseases related to bone loss such as osteoporosis, rheumatoidarthritis and the like (patent document 2).

In addition, it is suggested that orexin receptor agonist is useful forthe prophylaxis or treatment of sepsis, severe sepsis and septic shock,since the mortality was significantly improved by mere continuousadministration of orexin from the periphery in septic shock model mouse(patent document 3).

Therefore, a compound having an orexin type 2 receptor agonist activityis expected to be useful as a novel therapeutic drug for narcolepsy,idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbanceof consciousness such as coma and the like, narcolepsy syndromeaccompanied by narcolepsy-like symptoms, hypersomnia syndromeaccompanied by daytime hypersomnia (e.g., Parkinson's disease,Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer, obesity,insulin resistance syndrome, cardiac failure, diseases related to boneloss, sepsis and the like, further, anesthetic antagonist, aprophylactic or therapeutic drug for side effects and complications dueto anesthesia.

As sulfonamide derivatives, a compound represented by the formula

wherein each symbol is as described in the document (Patent Document 4)has been reported.

In addition, as compounds having an orexin type 2 receptor agonistactivity, the following compounds have been reported.

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 5).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 6).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 7).

A compound represented by the formula

wherein each symbol is as described in the document (Patent Document 8).

However, it is considered that these compounds are not satisfactory interms of activity, pharmacokinetics or safety, and the development of acompound having an orexin type 2 receptor agonist activity is stilldesired.

DOCUMENT LIST Patent Document

-   [Patent Document 1] WO 2015/073707 A1-   [Patent Document 2] WO 2015/048091 A1-   [Patent Document 3] WO 2015/147240 A1-   [Patent Document 4] WO 2012/137982 A9-   [Patent Document 5] WO 2015/088000 A1-   [Patent Document 6] WO 2016/133160 A1-   [Patent Document 7] WO 2016/199906 A1-   [Patent Document 8] WO 2017/135306 A1

Non-Patent Document

-   [Non-Patent Document 1] Cell, Vol. 92, 573-585, 1998-   [Non-Patent Document 2] Cell, Vol. 98, 365-376, 1999-   [Non-Patent Document 3] Proc. Natl. Acad. Sci. USA, Vol. 101,    4649-4654, 2004-   [Non-Patent Document 4] Cell, Vol. 98, 437-451, 1999-   [Non-Patent Document 5] Neuron, Vol. 38, 715-730, 2003-   [Non-Patent Document 6] CNS Drugs, Vol. 27, 83-90, 2013-   [Non-Patent Document 7] Cell Metabolism, Vol. 9, 64-76, 2009-   [Non-Patent Document 8] Neuroscience, Vol. 121, 855-863, 2003-   [Non-Patent Document 9] Respiration, Vol. 71, 575-579, 2004-   [Non-Patent Document 10] Peptides, Vol. 23, 1683-1688, 2002-   [Non-Patent Document 11] Journal of the American College of    Cardiology. Vol. 66, 2015, Pages 2522-2533-   [Non-Patent Document 12] Brain. Vol. 130, 2007, Pages 1586-1595

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a heterocyclic compound having anorexin type 2 receptor agonist activity.

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) or a salt thereof (sometimes to be referred to ascompound (I) in the present specification) has an orexin type 2 receptoragonist activity. As a result of further studies, they have completedthe present invention.

Accordingly, the present invention provides the following.

[1] A compound represented by the formula:

whereinR¹ is an acyl group or a hydrogen atom;R² is an optionally substituted 3- to 6-membered saturated cyclic group;R³ is an optionally substituted C₁₋₆ alkyl group, a mono- or di-C₁₋₆alkylamino group or a C₃₋₆ cycloalkyl group; andRing A is an azetidine ring or a pyrrolidine ring, each optionallyfurther substituted,or a salt thereof.[2] The compound or salt of the above-mentioned [1], wherein R¹ is(1) a C₁₋₆ alkoxy-carbonyl group,(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom and a hydroxy group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group,(4) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(5) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, or(6) a hydrogen atom;

R² is

(1) a C₃₋₆ cycloalkyl group optionally substituted by C₆₋₁₄ arylgroup(s) optionally substituted by 1 to 3 optionally halogenated C₁₋₆alkyl groups, or(2) a 3- to 6-membered saturated monocyclic non-aromatic heterocyclicgroup optionally substituted by 5- to 14-membered aromatic heterocyclicgroup(s) optionally substituted by 1 to 3 halogen atoms;R³ is a C₁₋₆ alkyl group; andRing A is a pyrrolidine ring.[3] The compound or salt of the above-mentioned [1], wherein R¹ is(1) an azetidinylcarbonyl group,(2) a cyclobutylcarbonyl group,(3) a mono- or di-C₁₋₆ alkyl-carbamoyl-group, or(4) a C₁₋₆ alkoxy-carbonyl group;R² is a C₃₋₆ cycloalkyl group substituted by one C₆₋₁₄ aryl group;R³ is a C₁₋₆ alkyl group; andRing A is a pyrrolidine ring.[4] The compound or salt of the above-mentioned [1], wherein R¹ is(1) an azetidinylcarbonyl group,(2) a cyclobutylcarbonyl group, or(3) a mono- or di-C₁₋₆ alkyl-carbamoyl group;R² is a C₃₋₆ cycloalkyl group substituted by one C₆₋₁₄ aryl group;R³ is a C₁₋₆ alkyl group; andRing A is a pyrrolidine ring.[5]N-(cis-1-(Azetidin-1-ylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide,or a salt thereof.[6]N-(cis-1-(Cyclobutylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide,or a salt thereof.[7]cis-N,N-Dimethyl-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide,or a salt thereof.[8] A medicament comprising the compound or salt of any of theabove-mentioned [1]-[7].[9] The medicament of the above-mentioned [8], which is an orexin type 2receptor agonist.[10] The medicament of the above-mentioned [8], which is an agent forthe prophylaxis or treatment of narcolepsy.[11] The compound or salt of any of the above-mentioned [1]-[7] for usein the prophylaxis or treatment of narcolepsy.[12] A method of activating an orexin type 2 receptor in a mammal, whichcomprises administering an effective amount of the compound or salt ofany of the above-mentioned [1]-[7] to the mammal.[13] A method for the prophylaxis or treatment of narcolepsy in amammal, which comprises administering an effective amount of thecompound or salt of any of the above-mentioned [1]-[7] to the mammal.[14] Use of the compound or salt of any of the above-mentioned [1]-[7]for the manufacture of an agent for the prophylaxis or treatment ofnarcolepsy.

Effect of the Invention

The compound of the present invention has an orexin type 2 receptoragonist activity, and is useful as an agent for the prophylaxis ortreatment of narcolepsy.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl. In the presentspecification, examples of the “C₁₋₁₆ aralkyl-carbonyl group” includephenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinyltarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent group A.

[Substituent Group A]

(1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) anoptionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group, and,(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5-to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic)aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi- ortri-cyclic) non-aromatic heterocyclic groups such asdihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl,dihydrobenzothiazolyl, dihydrobenzisothiazolyl,dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl,4H-quinolizinyl, indolinyl, isoindolinyl,tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl) amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino) and a (C₁₋₆alkyl) (C₆₋₁₄ aryl-carbonyl) amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆-14 aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from Substituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from Substituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., 25 diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from Substituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxy group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a C₁₋₆ alkylsulfonyl groupand a C₆₋₁₄ arylsulfonyl group, each of which optionally has 1 to 3substituents selected from Substituent group A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₃₋₆ cycloalkyl group”include a group having 3 to 6 carbon atoms, from among theabove-mentioned “C₃₋₁₀ cycloalkyl group”.

In the present specification, examples of the “3- to 6-memberedsaturated cyclic group” include a group having 3 to 6 carbon atoms (aC₃₋₆ cycloalkyl group), from among the above-mentioned “C₃₋₁₀ cycloalkylgroup”, and a 3- to 6-membered saturated group (a 3- to 6-memberedsaturated monocyclic non-aromatic heterocyclic group), from among theabove-mentioned “3- to 8-membered monocyclic non-aromatic heterocyclicgroup”.

In the present specification, examples of the “mono- or di-C₁₋₆alkylamino group” include an amino group mono- or di-substituted by theabove-mentioned “C₁₋₆ alkyl group”. In the case of a di-C₁₋₆ alkylaminogroup, the two C₁₋₆ alkyl groups may be the same or different (e.g.,N-ethyl-N-methylamino, etc.).

The definition of each symbol in the formula (I) is explained in detailin the following.

R¹ is an acyl group or a hydrogen atom.

Examples of the “acyl group” represented by R¹ include those exemplifiedas the above-mentioned “acyl group”.

R¹ is preferably

(1) an optionally substituted C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl),(2) an optionally substituted C₁₋₆ alkyl-carbonyl group (e.g.,propanoyl),(3) an optionally substituted C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclopropylcarbonyl), or(4) a hydrogen atom.

Examples of the substituent of the above-mentioned “optionallysubstituted C₁₋₆ alkoxy-carbonyl group”, “optionally substituted C₁₋₆alkyl-carbonyl group” and “optionally substituted C₃₋₁₀cycloalkyl-carbonyl group” include those exemplified as theabove-mentioned “substituent”, and preferred is a halogen atom (e.g., afluorine atom).

R¹ is more preferably

(1) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl),(2) a C₁₋₆ alkyl-carbonyl group (e.g., propanoyl) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),(3) a C₃₋₁₀ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), or(4) a hydrogen atom.

R¹ is particularly preferably a C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl).

As another embodiment, R¹ is preferably

(1) a hydrogen atom,(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1 to 7substituents selected from (i) a halogen atom, (ii) a cyano group, (iii)a hydroxy group, (iv) a C₃₋₁₀ cycloalkyl group, (v) a C₁₋₆ alkoxy group,(vi) a C₆₋₁₄ aryl group, (vii) a C₆₋₁₄ aryloxy group, (viii) a 5- to14-membered aromatic heterocyclic group (e.g., a pyrazolyl group, athiazolyl group, a pyrimidinyl group or a pyridazinyl group) optionallysubstituted by oxo group(s), (ix) a 5- to 14-membered aromaticheterocyclyloxy group (e.g., a pyrazolyloxy group) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkyl group, (x)a C₁₋₆ alkyl-carbonyl group, (xi) a C₁₋₆ alkoxy-carbonyl group, (xii) aC₁₋₆ alkyl-carbonyloxy group, (xiii) a C₁₋₆ alkylsulfonyl group, (xiv) amono- or di-C₁₋₆ alkylamino group, (xv) a C₁₋₆ alkyl-carbonylamino groupand (xvi) a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom, a cyano group, a hydroxygroup, an oxo group and a C₁₋₆ alkyl group,(4) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to 6substituents selected from a deuterium, a halogen atom and a C₆₋₁₄ arylgroup,(5) a C₃₋₁₀ cycloalkyloxy-carbonyl group optionally substituted by 1 to3 substituents selected from a C₁₋₆ alkyl group,(6) a C₆₋₁₄ aryl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom and a C₆₋₁₄ aryl group,(7) a C₆₋₁₄ aryloxy-carbonyl group,(8) a 5- to 14-membered aromatic heterocyclylcarbonyl group (e.g., afurylcarbonyl group, a thienylcarbonyl group, a pyrazolylcarbonyl group,an isoxazolylcarbonyl group or a pyridylcarbonyl group) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkyl group,(9) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group (e.g.,an azetidinylcarbonyl group, an oxetanylcarbonyl group, apyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, atetrahydropyranylcarbonyl group or a morpholinylcarbonyl group)optionally substituted by 1 to 3 substituents selected from an oxogroup, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group and aC₁₋₆ alkylsulfonyl group,(10) a mono- or di-C₁₋₆ alkyl-carbamoyl group optionally substituted by1 to 3 substituents selected from a halogen atom, a cyano group, ahydroxy group and a C₁₋₆ alkoxy group,(11) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group,(12) a mono- or di-C₆₋₁₄ aryl-carbamoyl group,(13) a C₁₋₆ alkylsulfonyl group,(14) a C₃₋₁₀ cycloalkylsulfonyl group,(15) a C₆₋₁₄ arylsulfonyl group optionally substituted by 1 to 3 halogenatoms,(16) a heterocycle-sulfonyl group (e.g., a thienylsulfonyl group, apyrazolylsulfonyl group, an imidazolylsulfonyl group, a pyridylsulfonylgroup or a dihydrochromenylsulfonyl group) optionally substituted by 1to 3 substituents selected from a C₁₋₆ alkyl group,(17) a mono- or di-C₁₋₆ alkyl-sulfamoyl group or (18) a C₁₋₆alkyl-carbonyl-carbonyl group.

As another embodiment, R¹ is preferably

(1) an optionally substituted C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl),(2) an optionally substituted C₁₋₆ alkyl-carbonyl group (e.g.,propanoyl, 2-methylpropanoyl),(3) an optionally substituted C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclopropylcarbonyl, cyclobutylcarbonyl),(4) an optionally substituted mono- or di-C₁₋₆ alkyl-carbamoyl group(e.g., dimethylcarbamoyl),(5) an optionally substituted 3- to 14-membered non-aromaticheterocyclylcarbonyl group (preferably a 3- to 8-membered monocyclicnon-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl)), or(6) a hydrogen atom.

Examples of the substituent of the above-mentioned “optionallysubstituted C₁₋₆ alkoxy-carbonyl group”, “optionally substituted C₁₋₆alkyl-carbonyl group”, “optionally substituted C₃₋₁₀ cycloalkyl-carbonylgroup”, “optionally substituted mono- or di-C₁₋₆ alkyl-carbamoyl group”and “optionally substituted 3-to 14-membered non-aromaticheterocyclylcarbonyl group” include those exemplified as theabove-mentioned “substituent”, and preferred are a halogen atom (e.g., afluorine atom) and a hydroxy group.

In this embodiment, R¹ is more preferably

(1) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl),(2) a C₁₋₆ alkyl-carbonyl group (e.g., propanoyl, 2-methylpropanoyl)optionally substituted by 1 to 3 substituents selected from a halogenatom (e.g., a fluorine atom) and a hydroxy group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl),(4) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl),(5) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group(preferably a 3- to 8-membered monocyclic non-aromaticheterocyclylcarbonyl group (e.g., azetidinylcarbonyl)), or(6) a hydrogen atom.

In this embodiment, R¹ is still more preferably

(1) an azetidinylcarbonyl group,(2) a cyclobutylcarbonyl group,(3) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl),or(4) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl).

In this embodiment, R¹ is particularly preferably

(1) an azetidinylcarbonyl group,(2) a cyclobutylcarbonyl group, or(3) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl).

R² is an optionally substituted 3- to 6-membered saturated cyclic group.

Examples of the “3- to 6-membered saturated cyclic group” of the“optionally substituted 3- to 6-membered saturated cyclic group”represented by R² include a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) anda 3- to 6-membered saturated monocyclic non-aromatic heterocyclic group(e.g., a pyrrolidinyl group, a piperidinyl group or a dioxanyl group).

Examples of the substituent of the “optionally substituted 3- to6-membered saturated cyclic group” represented by R² include thoseexemplified as the above-mentioned “substituent”, and preferred are anoptionally substituted C₆₋₁₄ aryl group (e.g., phenyl) and an optionallysubstituted 5- to 14-membered aromatic heterocyclic group (preferably a5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrimidinyl)), and more preferred are

(1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3optionally halogenated C₁₋₆ alkyl groups (e.g., trifluoromethyl), and(2) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or6-membered monocyclic aromatic heterocyclic group (e.g., pyrimidinyl))optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),and particularly preferred is a C₆₋₁₄ aryl group (e.g., phenyl).

In the present specification, when the “optionally substituted 3- to6-membered saturated cyclic group” represented by R² is the “3- to6-membered saturated cyclic group” having two substituents on the singleconstituting carbon thereof, the two substituents are optionally bondedto each other to form a spiro ring (e.g.,3H-spiro[2-benzofuran-1,1′-cyclohexane]-4′-yl,1,4-dioxaspiro[4.5]dec-8-yl) together with the “3- to 6-memberedsaturated cyclic group”, and such embodiment is encompassed in the“optionally substituted 3- to 6-membered saturated cyclic group”.

R² is preferably a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) or a 3- to6-membered saturated monocyclic non-aromatic heterocyclic group, eachoptionally substituted by 1 to 3 “optionally substituted C₆₋₁₄ arylgroups (e.g., phenyl)”.

R² is more preferably a C₃₋₆ cycloalkyl group (e.g., cyclohexyl)optionally substituted by 1 to 3 “optionally substituted C₆₋₁₄ arylgroups (e.g., phenyl)”.

R² is still more preferably a C₃₋₆ cycloalkyl group (e.g., cyclohexyl)optionally substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl).

R² is even more preferably a C₃₋₆ cycloalkyl group (e.g., cyclohexyl)substituted (preferably substituted at the 4-position) by one C₆₋₁₄ arylgroup (e.g., phenyl).

As another embodiment, R² is more preferably a C₃₋₆ cycloalkyl group ora 3- to 6-membered saturated monocyclic non-aromatic heterocyclic group(e.g., a pyrrolidinyl group, a piperidinyl group or a dioxanyl group),each optionally substituted by 1 to 3 substituents selected from

-   -   (1) a deuterium,    -   (2) a halogen atom,    -   (3) a hydroxy group,    -   (4) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom and a C₁₋₁₄ aryl        group,    -   (5) a C₃₋₁₀ cycloalkyl group,    -   (6) a C₁₋₆ alkoxy group optionally substituted by C₃₋₁₀        cycloalkyl group(s),    -   (7) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from a halogen atom, a cyano group, a C₁₋₆        alkyl group optionally substituted by 1 to 3 halogen atoms, a        C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and a hydroxy group,    -   (8) a C₆₋₁₄ aryloxy group,    -   (9) a tri-C₁₋₆ alkyl silyloxy group,    -   (10) a 5- to 14-membered aromatic heterocyclic group (e.g., a        pyrazolyl group, a thiazolyl group, a pyridyl group, a        pyrimidinyl group, a quinazolinyl group, a benzothiazolyl group        or an isoquinolinyl group) optionally substituted by 1 to 3        substituents selected from a halogen atom, a C₁₋₆ alkyl group        and a C₁₋₆ alkoxy group, and    -   (11) a C₆₋₁₄ aryl-carbonyl group.

As another embodiment, R² is preferably

(1) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted by1 to 3 “optionally substituted C₆₋₁₄ aryl groups (e.g., phenyl)”, or(2) a 3- to 6-membered saturated monocyclic non-aromatic heterocyclicgroup (e.g., piperidinyl) optionally substituted by 1 to 3 “optionallysubstituted 5- to 14-membered aromatic heterocyclic groups (preferably5- or 6-membered monocyclic aromatic heterocyclic groups (e.g.,pyrimidinyl))”.

In this embodiment, R² is more preferably

(1) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted byC₆₋₁₄ aryl group(s) (e.g., phenyl) optionally substituted by 1 to 3optionally halogenated C₁₋₆ alkyl groups (e.g., trifluoromethyl), or(2) a 3- to 6-membered saturated monocyclic non-aromatic heterocyclicgroup (e.g., piperidinyl) optionally substituted by 5- to 14-memberedaromatic heterocyclic group(s) (preferably 5- or 6-membered monocyclicaromatic heterocyclic group(s) (e.g., pyrimidinyl)) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

In this embodiment, R² is still more preferably a C₃₋₆ cycloalkyl group(e.g., cyclohexyl) substituted by one C₆₋₁₄ aryl group (e.g., phenyl).

In this embodiment, R² is even more preferably cyclohexyl substituted atthe 4-position by one C₆₋₁₄ aryl group (e.g., phenyl).

In this embodiment, R² is particularly preferably 4-phenylcyclohexyl.

R³ is an optionally substituted C₁₋₆ alkyl group, a mono- or di-C₁₋₆alkylamino group or a C₃₋₆ cycloalkyl group.

Examples of the substituent of the “optionally substituted C₁₋₆ alkylgroup” represented by R³ include those exemplified as theabove-mentioned “substituent”.

R³ is preferably an optionally substituted C₁₋₆ alkyl group (e.g.,methyl).

R³ is more preferably a C₁₋₆ alkyl group (e.g., methyl).

As another embodiment, R³ is preferably a C₁₋₆ alkyl group, or a mono-or di-C₁₋₆ alkylamino group.

Ring A is an azetidine ring or a pyrrolidine ring, each optionallyfurther substituted.

Examples of the substituent of the “azetidine ring or pyrrolidine ring,each optionally further substituted” represented by Ring A include thoseexemplified as the above-mentioned “substituent”.

Ring A is preferably an optionally further substituted pyrrolidine ring.

Ring A is more preferably a pyrrolidine ring.

As another embodiment, Ring A is preferably an azetidine ring or apyrrolidine ring.

Regarding Ring A of compound (I), the configuration based on the carbonatom that —NHSO₂R³ is bonded to and the carbon atom that —CH₂—O—R² isbonded to (i.e., the configuration based on the 2- and 3-positions onthe azetidine ring or the pyrrolidine ring) is preferably cis-form. Thatis, compound (I) is preferably represented by the formula (Ia) or (Ib):

wherein each symbol is as defined above,more preferably represented by the formula (Ia):

wherein each symbol is as defined above.

Preferable embodiments of compound (I) include the following compounds.

[Compound A-1]

Compound (I) wherein

R¹ is

(1) an optionally substituted C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl),(2) an optionally substituted C₁₋₆ alkyl-carbonyl group (e.g.,propanoyl),(3) an optionally substituted C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclopropylcarbonyl), or(4) a hydrogen atom;R² is a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 3 “optionally substituted C₆₋₁₄ aryl groups (e.g., phenyl)”;R³ is an optionally substituted C₁₋₆ alkyl group (e.g., methyl); andRing A is an optionally further substituted pyrrolidine ring.

[Compound B-1]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl),(2) a C₁₋₆ alkyl-carbonyl group (e.g., propanoyl) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),(3) a C₃₋₁₀ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), or(4) a hydrogen atom;R² is a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl);R³ is a C₁₋₆ alkyl group (e.g., methyl); and Ring A is a pyrrolidinering.

[Compound C-1]

Compound (I) wherein

R¹ is a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl);R² is a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) substituted (preferablysubstituted at the 4-position) by one C₆₋₁₄ aryl group (e.g., phenyl);R³ is a C₁₋₆ alkyl group (e.g., methyl); andRing A is a pyrrolidine ring.

[Compound D-1]

Compound (I) wherein

R¹ is

(1) a hydrogen atom,(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1 to 7substituents selected from (i) a halogen atom, (ii) a cyano group, (iii)a hydroxy group, (iv) a C₃₋₁₀ cycloalkyl group, (v) a C₁₋₆ alkoxy group,(vi) a C₆₋₁₄ aryl group, (vii) a C₆₋₁₄ aryloxy group, (viii) a 5- to14-membered aromatic heterocyclic group (e.g., a pyrazolyl group, athiazolyl group, a pyrimidinyl group or a pyridazinyl group) optionallysubstituted by oxo group(s), (ix) a 5- to 14-membered aromaticheterocyclyloxy group (e.g., a pyrazolyloxy group) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkyl group, (x)a C₁₋₆ alkyl-carbonyl group, (xi) a C₁₋₆ alkoxy-carbonyl group, (xii) aC₁₋₆ alkyl-carbonyloxy group, (xiii) a C₁₋₆ alkylsulfonyl group, (xiv) amono- or di-C₁₋₆ alkylamino group, (xv) a C₁₋₆ alkyl-carbonylamino groupand (xvi) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom, a cyano group, a hydroxygroup, an oxo group and a C₁₋₆ alkyl group,(4) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to 6substituents selected from a deuterium, a halogen atom and a C₆₋₁₄ arylgroup,(5) a C₃₋₁₀ cycloalkyloxy-carbonyl group optionally substituted by 1 to3 substituents selected from a C₁₋₆ alkyl group,(6) a C₆₋₁₄ aryl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom and a C₆₋₁₄ aryl group,(7) a C₆₋₁₄ aryloxy-carbonyl group,(8) a 5- to 14-membered aromatic heterocyclylcarbonyl group (e.g., afurylcarbonyl group, a thienylcarbonyl group, a pyrazolylcarbonyl group,an isoxazolylcarbonyl group or a pyridylcarbonyl group) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkyl group,(9) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group (e.g.,an azetidinylcarbonyl group, an oxetanylcarbonyl group, apyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, atetrahydropyranylcarbonyl group or a morpholinylcarbonyl group)optionally substituted by 1 to 3 substituents selected from an oxogroup, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group and aC₁₋₆ alkylsulfonyl group,(10) a mono- or di-C₁₋₆ alkyl-carbamoyl group optionally substituted by1 to 3 substituents selected from a halogen atom, a cyano group, ahydroxy group and a C₁₋₆ alkoxy group,(11) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group,(12) a mono- or di-C₆₋₁₄ aryl-carbamoyl group,(13) a C₁₋₆ alkylsulfonyl group,(14) a C₃₋₁₀ cycloalkylsulfonyl group,(15) a C₆₋₁₄ arylsulfonyl group optionally substituted by 1 to 3 halogenatoms,(16) a heterocycle-sulfonyl group (e.g., a thienylsulfonyl group, apyrazolylsulfonyl group, an imidazolylsulfonyl group, a pyridylsulfonylgroup or a dihydrochromenylsulfonyl group) optionally substituted by 1to 3 substituents selected from a C₁₋₆ alkyl group,(17) a mono- or di-C₁₋₆ alkyl-sulfamoyl group or(18) a C₁₋₆ alkyl-carbonyl-carbonyl group;R² is a C₃₋₆ cycloalkyl group or a 3- to 6-membered saturated monocyclicnon-aromatic heterocyclic group (e.g., a pyrrolidinyl group, apiperidinyl group or a dioxanyl group), each optionally substituted by 1to 3 substituents selected from

-   -   (1) a deuterium,    -   (2) a halogen atom,    -   (3) a hydroxy group,    -   (4) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom and a C₆₋₁₄ aryl        group,    -   (5) a C₃₋₁₀ cycloalkyl group,    -   (6) a C₁₋₆ alkoxy group optionally substituted by C₃₋₁₀        cycloalkyl group(s),    -   (7) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from a halogen atom, a cyano group, a C₁₋₆        alkyl group optionally substituted by 1 to 3 halogen atoms, a        C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and a hydroxy group,    -   (8) a C₆₋₁₄ aryloxy group,    -   (9) a tri-C₁₋₆ alkyl silyloxy group,    -   (10) a 5- to 14-membered aromatic heterocyclic group (e.g., a        pyrazolyl group, a thiazolyl group, a pyridyl group, a        pyrimidinyl group, a quinazolinyl group, a benzothiazolyl group        or an isoquinolinyl group) optionally substituted by 1 to 3        substituents selected from a halogen atom, a C₁₋₆ alkyl group        and a C₁₋₆ alkoxy group, and    -   (11) a C₆₋₁₄ aryl-carbonyl group;        R³ is a C₁₋₆ alkyl group, or a mono- or di-C₁₋₆ alkylamino        group; and        Ring A is an azetidine ring or a pyrrolidine ring.

[Compound A-2]

Compound (I) wherein

R¹ is

(1) an optionally substituted C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl),(2) an optionally substituted C₁₋₆ alkyl-carbonyl group (e.g.,propanoyl, 2-methylpropanoyl),(3) an optionally substituted C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclopropylcarbonyl, cyclobutylcarbonyl),(4) an optionally substituted mono- or di-C₁₋₆ alkyl-carbamoyl group(e.g., dimethylcarbamoyl),(5) an optionally substituted 3- to 14-membered non-aromaticheterocyclylcarbonyl group (preferably a 3- to 8-membered monocyclicnon-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl)), or(6) a hydrogen atom;

R² is

(1) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted by1 to 3 “optionally substituted C₆₋₁₄ aryl groups (e.g., phenyl)”, or(2) a 3- to 6-membered saturated monocyclic non-aromatic heterocyclicgroup (e.g., piperidinyl) optionally substituted by 1 to 3 “optionallysubstituted 5- to 14-membered aromatic heterocyclic groups (preferably5- or 6-membered monocyclic aromatic heterocyclic groups (e.g.,pyrimidinyl))”;R³ is an optionally substituted C₁₋₆ alkyl group (e.g., methyl); andRing A is an optionally further substituted pyrrolidine ring.

[Compound B-2]

Compound (I) wherein

R¹ is

(1) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl),(2) a C₁₋₆ alkyl-carbonyl group (e.g., propanoyl, 2-methylpropanoyl)optionally substituted by 1 to 3 substituents selected from a halogenatom (e.g., a fluorine atom) and a hydroxy group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl),(4) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl),(5) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group(preferably a 3- to 8-membered monocyclic non-aromaticheterocyclylcarbonyl group (e.g., azetidinylcarbonyl)), or(6) a hydrogen atom;

R² is

(1) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted byC₆₋₁₄ aryl group(s) (e.g., phenyl) optionally substituted by 1 to 3optionally halogenated C₁₋₆ alkyl groups (e.g., trifluoromethyl), or(2) a 3- to 6-membered saturated monocyclic non-aromatic heterocyclicgroup (e.g., piperidinyl) optionally substituted by 5- to 14-memberedaromatic heterocyclic group(s) (preferably 5- or 6-membered monocyclicaromatic heterocyclic group(s) (e.g., pyrimidinyl)) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom);R³ is a C₁₋₆ alkyl group (e.g., methyl); and Ring A is a pyrrolidinering.

[Compound C-2]

Compound (I) wherein

R¹ is

(1) an azetidinylcarbonyl group,(2) a cyclobutylcarbonyl group,(3) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl),or(4) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl);R² is a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) substituted by oneC₆₋₁₄ aryl group (e.g., phenyl) [preferably cyclohexyl substituted atthe 4-position by one C₆₋₁₄ aryl group (e.g., phenyl), particularlypreferably 4-phenylcyclohexyl];R³ is a C₁₋₆ alkyl group (e.g., methyl); andRing A is a pyrrolidine ring.

[Compound D-2]

Compound (I) wherein

R¹ is

(1) an azetidinylcarbonyl group,(2) a cyclobutylcarbonyl group, or(3) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., dimethylcarbamoyl);R² is a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) substituted by oneC₆₋₁₄ aryl group (e.g., phenyl) [preferably cyclohexyl substituted atthe 4-position by one C₆₋₁₄ aryl group (e.g., phenyl), particularlypreferably 4-phenylcyclohexyl];R³ is a C₁₋₆ alkyl group (e.g., methyl); andRing A is a pyrrolidine ring.

[Compound E]

-   N-(cis-1-(azetidin-1-ylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide,    or a salt thereof.-   N-(cis-1-(cyclobutylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide,    or a salt thereof.-   cis-N,N-dimethyl-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide,    or a salt thereof.

Specific examples of compound (I) include the compounds of thebelow-mentioned Examples 1 to 11.

As a salt of a compound represented by the formula (I), apharmacologically acceptable salt is preferable, and examples of suchsalt include a salt with inorganic base, a salt with organic base, asalt with inorganic acid, a salt with organic acid, a salt with basic oracidic amino acid and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like, alkaline earthmetal salts such as calcium salt, magnesium salt and the like, aluminumsalt, ammonium salt and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine,tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, benzylamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like.

Preferable examples of the salt with acidic amino acid include saltswith aspartic acid, glutamic acid and the like.

The production method of the compound of the present invention isexplained below.

The raw material compound and reagent used and the compound obtained ineach step in the following production method may be each in a form of asalt, and examples of such salt include those similar to the salts ofthe compound represented by the formula (I).

When the compound obtained in each step is a free form, it can beconverted to the objective salt according to a method known per se. Whenthe compound obtained in each step is a salt, it can be converted to theobjective free form or the other salt according to a method known perse.

The compound obtained in each step can be used directly as the reactionmixture or as a crude product for the next reaction. Alternatively, thecompound obtained in each step can be isolated and purified from areaction mixture-according to a method known per se, for example, aseparation means such as concentration, crystallization,recrystallization, distillation, solvent extraction, fractionaldistillation, column chromatography and the like.

When the raw material compound and reagent used in each step arecommercially available, the commercially available product can also beused directly.

In the reaction in each step, while the reaction time varies dependingon the kind of the reagent and solvent to be used, it is generally 1min-48 hr, preferably 10 min-8 hr, unless otherwise specified.

In the reaction in each step, while the reaction temperature variesdepending-on the kind of the reagent and solvent to be used, it isgenerally −78° C.-300° C., preferably −78° C.-150° C., unless otherwisespecified.

In the reaction in each step, while the pressure varies depending on thekind of the reagent and solvent to be used, it is generally 1 atm-20atm, preferably 1 atm-3 atm, unless otherwise specified.

Microwave synthesizer such as Initiator manufactured by Biotage and thelike may be used for the reaction in each step. While the reactiontemperature varies depending on the kind of the reagent and solvent tobe used, it is generally room temperature −300° C., preferably 50°C.-250° C., unless otherwise specified. While the reaction time variesdepending on the kind of the reagent and solvent to be used, it isgenerally 1 min-48 hr, preferably 1 min-8 hr, unless otherwisespecified.

In the reaction in each step, the reagent is used in an amount of 0.5equivalents-20 equivalents, preferably 0.8 equivalents-5 equivalents,relative to the substrate, unless otherwise specified. When the reagentis used as a catalyst, the reagent is used in an amount of 0.001equivalent-1 equivalent, preferably 0.01 equivalent-0.2 equivalent,relative to the substrate. When the reagent is used as a reactionsolvent, the reagent is used in a solvent amount.

Unless otherwise specified, the reaction in each step is carried outwithout solvent, or by dissolving or suspending the raw materialcompound in a suitable solvent. Examples of the solvent include thosedescribed in Examples and the following solvents.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;saturated hydrocarbons: cyclohexane, hexane and the like; amides:N,N-dimethylformamide, N-methylpyrrolidone and the like;halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;nitriles: acetonitrile and the like;sulfoxides: dimethyl sulfoxide and the like;aromatic organic bases: pyridine and the like;anhydrides: acetic anhydride and the like;organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;inorganic acids: hydrochloric acid, sulfuric acid and the like;esters: ethyl acetate and the like;ketones: acetone, methyl ethyl ketone and the like; water.

The above-mentioned solvent can be used in a mixture of two or morekinds thereof in an appropriate ratio.

When a base is used for the reaction in each step, examples thereofinclude those described in Examples and the following bases.

inorganic bases: sodium hydroxide, magnesium hydroxide, sodiumcarbonate, calcium carbonate, sodium hydrogen carbonate and the like;organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;alkali metal hydrides: sodium hydride and the like;metal amides: sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like; organic lithiums: n-butyllithium andthe like.

When an acid or an acid catalyst is used for the reaction in each step,examples thereof include those described in Examples and the followingacids and acid catalysts. inorganic acids: hydrochloric acid, sulfuricacid, nitric acid, hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewisacid: boron trifluoride diethyl ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride andthe like.

Unless otherwise specified, the reaction in each step is carried outaccording to a method known per se, for example, the method described inJikken Kagaku Kouza, 5th Edition, vol. 13-19 (the Chemical Society ofJapan ed.); Shin Jikken Kagaku Kouza, vol. 14-15 (the Chemical Societyof Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F.Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the ReactionMechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANICSYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); ModernOrganic Synthesis in the Laboratory A Collection of StandardExperimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); ComprehensiveHeterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan); StrategicApplications of Named Reactions in Organic Synthesis (translated byKiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations(VCH Publishers Inc.), 1989, or the like, or the method described inExamples.

In each step, the protection or deprotection reaction of an functionalgroup is carried out according to a method known per se, for example,the method described in “Protective Groups in Organic Synthesis, 4thEd”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M.Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski), orthe like, or the method described in Examples.

Examples of the protecting group for a hydroxy group of an alcohol andthe like and a phenolic hydroxy group include ether-type protectinggroups such as methoxymethyl ether, benzyl ether,tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like;carboxylate ester-type protecting groups such as acetate ester and thelike; sulfonate ester-type protecting groups such as methanesulfonateester and the like; carbonate ester-type protecting groups such astert-butylcarbonate and the like, and the like.

Examples of the protecting group for a carbonyl group of an aldehydeinclude acetal-type protecting groups such as dimethylacetal and thelike; cyclic acetal-type protecting groups such as 1,3-dioxane and thelike, and the like.

Examples of the protecting group for a carbonyl group of a ketoneinclude ketal-type protecting groups such as dimethylketal and the like;cyclic ketal-type protecting groups such as 1,3-dioxane and the like;oxime-type protecting groups such as O-methyloxime and the like;hydrazone-type protecting groups such as N,N-dimethylhydrazone and thelike, and the like.

Examples of the protecting group for a carboxyl group include ester-typeprotecting groups such as methyl ester and the like; amide-typeprotecting groups such as N,N-dimethylamide and the like, and the like.

Examples of the protecting group for a thiol include ether-typeprotecting groups such as benzyl thioether and the like; ester-typeprotecting groups such as thioacetate ester, thiocarbonate,thiocarbamate and the like, and the like.

Examples of the protecting group for an amino group and an aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate-type protecting groups such as benzyl carbamate and the like;amide-type protecting groups such as acetamide and the like; alkylamine-type protecting groups such as N-triphenylmethylamine and thelike; sulfonamide-type protecting groups such as methanesulfonamide andthe like, and the like.

The protecting groups can be removed according to a method known per se,for example, by employing a method using acid, base, ultraviolet rays,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, areduction method, and the like.

When reduction reaction is carried out in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar's catalyst and the like may be employed.

When oxidation reaction is carried out in each step, examples of theoxidizing agent to be used include peroxides such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodates such as sodium periodate and the like;hypervalent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chromium such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When radical cyclization reaction is carried out in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. Examples of the radical reagent to be used includetributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane,diphenylsilane, samarium iodide and the like.

When Wittig reaction is carried out in each step, examples of the Wittigreagent to be used include alkylidene phosphoranes and the like. Thealkylidene phosphoranes can be prepared according to a method known perse, for example, by reacting a phosphonium salt with a strong base.

When Horner-Emmons reaction is carried out in each step, examples of thereagent to be used include phosphonoacetates such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like;and bases such as alkali metal hydrides, organic lithiums and the like.

When Friedel-Crafts reaction is carried out in each step, a combinationof a Lewis acid and an acid chloride or a combination of a Lewis acidand an alkylating agent (e.g., an alkyl halide, an alcohol, an olefinetc.) is used as a reagent. Alternatively, an organic acid or aninorganic acid can also be used instead of a Lewis acid, and ananhydride such as acetic anhydride and the like can also be used insteadof an acid chloride.

When aromatic nucleophilic substitution reaction is carried out in eachstep, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g.,an organic base etc.) are used as a reagent.

When nucleophilic addition reaction by a carbo anion, nucleophilic1,4-addition reaction (Michael addition reaction) by a carbo anion ornucleophilic substitution reaction by a carbo anion is carried out ineach step, and examples of the base to be used for generation of thecarbo anion include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

When Grignard reaction is carried out in each step, examples of theGrignard reagent to be used include arylmagnesium halides such asphenylmagnesium bromide and the like; and alkylmagnesium halides such asmethylmagnesium bromide and the like. The Grignard reagent can beprepared according to a method known per se, for example, by reacting analkyl halide or an aryl halide with a metal magnesium in an ether ortetrahydrofuran as a solvent.

When Knoevenagel condensation reaction is carried out in each step, acompound having an activated methylene group with two electronwithdrawing groups (e.g., malonic acid, diethyl malonate, malononitrileetc.) and a base (e.g., an organic base, a metal alkoxide, an inorganicbase) are used as a reagent.

When Vilsmeier-Haack reaction is carried out in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide etc.) areused as a reagent.

When azidation reaction of an alcohol, an alkyl halide or a sulfonate iscarried out in each step, examples of the azidating agent to be usedinclude diphenylphosphorylazide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, for the azidation reaction of analcohol, a method using diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method usingtrimethylsilylazide and a Lewis acid, and the like are employed.

When reductive amination reaction is carried out in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused include paraformaldehyde, aldehydes such as acetaldehyde and thelike, and ketones such as cyclohexanone and the like. When the substrateis a carbonyl compound, examples of the amine to be used includeammonia, primary amines such as methylamine and the like; secondaryamines such as dimethylamine and the like, and the like.

When Mitsunobu reaction is carried out in each step, an azodicarboxylate(e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate(DIAD) etc.) and triphenylphosphine are used as a reagent.

When esterification reaction, amidation reaction or urea formationreaction is carried out in each step, examples of the reagent to be usedinclude acyl halides such as acid chlorides, acid bromides and the like;activated carboxylic acids such as acid anhydrides, activated esters,sulfates and the like. Examples of the activating agent of thecarboxylic acid include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM) and the like; carbonate condensing agents such as1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide(DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOPreagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);thionyl chloride; lower alkyl haloformates such as ethyl chloroformateand the like; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid; combinations thereof andthe like. When carbodiimide condensing agent is used, an additive suchas 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be added to the reactionsystem.

When coupling reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride and thelike; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) andthe like; rhodium compounds such as tris(triphenylphosphine)rhodium(III)chloride and the like; cobalt compounds; copper compounds such as copperoxide, copper(I) iodide and the like; platinum compounds and the like.In addition, a base can be added to the reaction system, and examplesthereof include inorganic bases and the like.

When thiocarbonylation reaction is carried out in each step, phosphoruspentasulfide is typically used as the thiocarbonylating agent.Alternatively, a reagent having a1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g.,2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) etc.) can also be used instead of phosphoruspentasulfide.

When Wohl-Ziegler reaction is carried out in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. In addition, the reaction can be accelerated bysubjecting a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile and the like to the reaction system reaction.

When halogenation reaction of a hydroxy group is carried out in eachstep, examples of the halogenating agent to be used include hydrohalicacids and acid halides of inorganic acids, specifically, hydrochloricacid, thionyl chloride, phosphorus oxychloride and the like forchlorination, 48% hydrobromic acid and the like for bromination. Inaddition, a method of producing an alkyl halide by reacting an alcoholwith triphenylphosphine and carbon tetrachloride or carbon tetrabromideor the like can be employed. Alternatively, a method of producing analkyl halide via two steps comprising converting an alcohol to thecorresponding sulfonate, and then reacting the sulfonate with lithiumbromide, lithium chloride or sodium iodide can also be employed.

When Arbuzov reaction is carried out in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

When sulfonate esterification reaction is carried out in each step,examples of the sulfonating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride and the like.

When hydrolysis reaction is carried out in each step, an acid or a baseis used as a reagent. For acid hydrolysis reaction of tert-butyl ester,formic acid, triethylsilane and the like may be added toreductively-trap tert-butyl cation which is by-produced.

When dehydration reaction is carried out in each step, examples of thedehydrating agent to be used include sulfuric acid, diphosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

Among compound (9) used in the below-mentioned Scheme 3, compound (9)-1,which is compound (9) wherein Ring A is a pyrrolidine ring, is can beproduced from compound (1) according to the method shown in thefollowing Scheme 1. In the scheme, P¹ is a protecting group, and R² isas defined above.

Examples of the “protecting group” represented by P¹ include thoseexemplified as the above-mentioned “protecting group for an amino groupand an aromatic heterocycle such as imidazole, pyrrole, indole and thelike”.

Compound (1) may be commercially available, or can be produced accordingto a method known per se or a method analogous thereto.

Compound (2) can be produced by subjecting compound (1) to anucleophilic substitution reaction with halogenation allyl in thepresence of a base. Examples of the base to be used include alkali metalhydrides and the like.

Compound (4) can be produced by subjecting compound (3) to Streckerreaction. As the reagent, a cyanating agent such as sodium cyanide,potassium cyanide, trimethylsilylcyanide and the like, an ammonium saltsuch as anunonium chloride, ammonium formate, ammonium acetate and thelike, and an inorganic acid are used.

Compound (6) can be produced by subjecting compound (5) to acondensation reaction with Meldrum's acid. Examples of the reagent to beused include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid; combinations thereof, andthe like. When a carbodiimide condensing agent is used, an additive suchas 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be further added to thereaction system.

Compound (7) can be produced by subjecting compound (6) to a cyclizationreaction. An acid may be added to the reaction system, and examples ofthe acid include inorganic acids, organic acids and the like.

Compound (9) and compound (17), which are used in the below-mentionedScheme 3 and Scheme 5, respectively, can be produced from compound (10)according to the method shown in the following Scheme 2. In the scheme,R⁴ is an optionally substituted C₁₋₆ alkyl group or an optionallysubstituted C₆₋₁₄ aryl group, P² is a protecting group, LG¹ is a leavinggroup, and the other symbols are as defined above.

Examples of the “optionally substituted C₁₋₆ alkyl group” and the“optionally substituted C₆₋₁₄ aryl group” represented by R⁴ include theabove-mentioned “optionally substituted hydrocarbon group” wherein thehydrocarbon group is a C₁₋₆ alkyl group or a C₆₋₁₄ aryl group.

Examples of the “protecting group” represented by P² include thoseexemplified as the above-mentioned “protecting group for a hydroxy groupof an alcohol and the like and a phenolic hydroxy group”

Examples of the “leaving group” represented by LG¹ include halogenatoms, optionally halogenated C₁₋₆ alkylsulfonyloxy groups (e.g.,methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy),C₆₋₁₄ arylsulfonyloxy groups optionally substituted by C₁₋₆ alkyl (e.g.,benzenesulfonyloxy, toluenesulfonyloxy) and the like.

Compound (10) may be commercially available, or can be producedaccording to a method known per se or a method analogous thereto.

Compound (12) can be produced by subjecting compound (10) to anucleophilic substitution reaction with compound (11) in the presence ofa base. Examples of the base to be used include alkali metal hydrides,organic lithiums and the like. Alternatively, compound (12) can also beproduced by two step reaction, i.e., by converting compound (10) to thecorresponding enamine, and then reacting the enamine with compound (11).

Examples of the amine to be used for the enamine formation includepyrrolidine, morpholine, N,N-dimethylhydrazine and the like. A base maybe added to the reaction system of the enamine and compound (11).Examples of the base include alkali metal hydrides, organic lithiums andthe like.

Compound (16) can be produced by subjecting compound (14) to anucleophilic substitution reaction with compound (15) in the presence ofa base. Examples of the base to be used include alkali metal hydridesand the like.

Among compound (20) used in the below-mentioned Scheme 4, the cis-formcompound (20) and the trans-form compound (20) can be produced from thecis-form compound (9) according to the method shown in the followingScheme 3. In the scheme, R⁵, R⁶ and R⁷ are each independently anoptionally substituted C₁₋₆ alkyl group or an optionally substitutedC₆₋₁₄ aryl group, and the other symbols are as defined above.

Examples of the “optionally substituted C₁₋₆ alkyl group” and the“optionally substituted C₆₋₁₄ aryl group” represented by R⁵, R⁶ or R⁷include the above-mentioned “optionally substituted hydrocarbon group”wherein the hydrocarbon group is a C₁₋₆ alkyl group or a C₆₋₁₄ arylgroup.

The cis-form compound (9) can be produced according to the method shownin Scheme 1 or Scheme 2.

Compound (17) used in Scheme 5 can be produced by subjecting the azideof compound (20) to a reduction reaction, according to the method shownin the following Scheme 4. In the scheme, each symbol is as definedabove. Examples of the reagent to be used include phosphines such astriphenylphosphine and the like, and the like.

Compound (20) can be produced according to the method shown in Scheme 3.

Compound (I) can be produced from compound (17) according to the methodshown in the following Scheme 5. In the scheme, LG² and LG³ are eachindependently a leaving group, and the other symbols are as definedabove.

Examples of the “leaving group” represented by LG² or LG³ include thoseexemplified as the “leaving group” represented by LG¹.

Compound (17) can be produced according to the method shown in Scheme 2or Scheme 4.

Compound (22) can be produced by subjecting compound (17) to asulfonamidation reaction with compound (21) in the presence of a base.Examples of the base to be used include organic bases and the like.

Compound (I) can be produced by subjecting compound (I)-1 to acondensation reaction with compound (23). Examples of compound (23) tobe used include acyl halides such as acid chlorides, acid bromides,alkyl chloroformates, carbamoyl chlorides and the like; activatedcarboxylic acids such as acid anhydrides, activated esters, sulfateesters and the like. Examples of the activating agent for carboxylicacid include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid; combinations thereof, andthe like. In addition, a base may be added to the reaction system.Examples of the base include inorganic bases, organic bases and thelike. When a carbodiimide condensing agent is used, an additive such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be further added to thereaction system.

In the thus-obtained compound (I), an intramolecular functional groupcan also be converted to an object functional group by a combination ofchemical reactions known per se. Examples of the chemical reactioninclude oxidation reaction, reduction reaction, alkylation reaction,acylation reaction, ureation reaction, hydrolysis reaction, aminationreaction, esterification reaction, aryl coupling reaction, deprotectionreaction and the like.

In the above-mentioned production method, when a starting compound hasan amino group, a carboxyl group, a hydroxy group, a carbonyl group or amercapto group as a substituent, a protecting group generally used inthe peptide chemistry may be introduced into these groups, and theobject compound can be obtained by removing the protecting group asnecessary after the reaction.

Compound (I) obtained by the above-mentioned production method can beisolated and purified by a known means, such as solvent extraction,liquid conversion, phase transfer, crystallization, recrystallization,chromatography and the like.

When compound (I) contains optical isomer, stereoisomer, regio isomerand rotamer, these compounds are also included in compound (I), and eachcan be obtained as a single product by a synthesis method or aseparation method known per se. For example, when an optical isomerexists in compound (I), an optical isomer resolved from the compound isalso encompassed in compound (I).

Here, an optical isomer can be produced by a method known per se.

Compound (I) may be a crystal.

A crystal of compound (I) (hereinafter sometimes to be abbreviated asthe crystal of the present invention) can be produced by crystallizingcompound (I), by applying a crystallization method known per se.

In the present specification, the melting point means a melting pointmeasured, for example, by micro melting point apparatus (Yanako, MP-500Dor Buchi, B-545), DSC (differential scanning calorimetry analysis)apparatus (SEIKO, EXSTAR6000) and the like.

Generally, the melting point sometimes varies depending on themeasurement device, measurement condition and the like. The crystal inthe present specification may be a crystal showing a melting pointdifferent from the values described in the present specification as longas the difference is within a general error range.

The crystal of the present invention is superior in the physicochemicalproperties (e.g., melting point, solubility, stability) and biologicalproperties (e.g., pharmacokinetics (absorbability, distribution,metabolism, excretion), efficacy expression), and is extremely useful asa medicament.

Compound (I) may be used as a prodrug. A prodrug of the compound (I)means a compound which is converted to the compound (I) of the presentinvention with a reaction due to an enzyme, an gastric acid, etc. underthe physiological condition in the living body, that is, a compoundwhich is converted to the compound (I) of the present invention withoxidation, reduction, hydrolysis, etc. according to an enzyme; acompound which is converted to the compound (I) of the present inventionby hydrolysis etc. due to gastric acid, etc.

A prodrug of compound (I) may be a compound obtained by subjecting anamino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted intocompound (I) under a physiological condition, such as those described inIYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design ofMolecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, a prodrug may form a salt, and as suchsalt, those exemplified as a salt of the compound represented by theabove-mentioned formula (I) can be mentioned.

Compound (I) may be labeled with an isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸F,³⁵S, ¹²⁵I) and the like.

Compound (I) labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

Furthermore, compound (I) may be a hydrate or a non-hydrate, or anon-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Furthermore, compound (I) may be a pharmaceutically acceptable cocrystalor cocrystal salt. The cocrystal or cocrystal salt means a crystallinesubstance constituted with two or more special solids at roomtemperature, each having different physical properties (e.g., structure,melting point, melting heat, hygroscopicity, solubility and stability).The cocrystal or cocrystal salt can be produced by a cocrystallizationmethod known per se.

Compound (I) or a prodrug thereof (hereinafter sometimes to be simplyabbreviated as the compound of the present invention) can be used as itis or in the form of a pharmaceutical composition (also referred to as amedicament) by mixing with a pharmacologically acceptable carrier etc.to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse,swine, monkey) as an agent for the prophylaxis or treatment of variousdiseases mentioned below.

As pharmacologically acceptable carriers, various organic or inorganiccarrier substances conventionally used as preparation materials can beused. These are incorporated as excipient, lubricant, binder anddisintegrant for solid preparations; or solvent, solubilizing agent,suspending agent, isotonicity agent, buffer and soothing agent forliquid preparations; and the like; and preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canbe added as necessary.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, pullulan, light anhydrous silicicacid, synthetic aluminum silicate and magnesium alumino metasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinated starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizing agent include polyethyleneglycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like, polysorbates; and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers of phosphate, acetate,carbonate, citrate etc.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the antioxidant include sulfite salts andascorbate salts.

Preferable examples of the colorant include aqueous food tar colors(e.g., food colors such as Food Color Red Nos. 2 and 3, Food ColorYellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like foodcolors), water insoluble lake dyes (e.g., aluminum salt of theabove-mentioned aqueous food tar color), natural dyes (e.g., β-carotene,chlorophyll, red iron oxide) and the like.

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the above-mentioned pharmaceuticalcomposition include oral preparations such as tablet (includingsugar-coated tablet, film-coated tablet, sublingual tablet, orallydisintegrating tablet, buccal tablet), capsule (including soft capsule,microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion,suspension, aerosol, films (e.g., orally disintegrable films, oralmucosa-adhesive film) and the like; and parenteral agents such asinjection (e.g., subcutaneous injection, intravenous injection,intramuscular injection, intraperitoneal injection, drip infusion),external preparation (e.g., transdermal absorption type preparation,ointment, lotion, adhesive preparation), suppository (e.g., rectalsuppository, vaginal suppository), pellet, nasal preparation, pulmonarypreparation (inhalant), eye drop and the like. The compound andmedicament of the present invention can be respectively safelyadministered orally or parenterally (e.g., intrarectal, intravenous,intraarterial, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intravaginal, intraperitoneal,intratumoral, proximal tumor administrations, and administration to thelesion).

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical formulation, forexample, the method described in the Japanese Pharmacopoeia, and thelike.

While the content of the compound of the present invention in thepharmaceutical composition of the present invention varies depending onthe dosage form, dose of the compound of the present invention and thelike, it is, for example, about 0.1 to 100 wt %.

When an oral preparation is produced, coating may be applied wherenecessary for the purpose of taste masking, enteric solubility orsustainability.

Examples of the coating base used for coating include sugar coatingbase, water-soluble film coating base, enteric film coating base, andsustained-release film coating base.

As the sugar coating base, sucrose is used, and one or more kindsselected from talc, and the precipitated calcium carbonate, gelatin, gumarabic, pullulan, carnauba wax and the like may be further used incombination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose and the like;synthetic polymers such as polyvinyl acetal diethylaminoacetate,aminoalkylmethacrylate copolymer E [Eudragit E (trade name)],polyvinylpyrrolidone and the like; and polysaccharides such as pullulanand the like.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L(trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (tradename)], methacrylic acid copolymer S [Eudragit S (trade name)] and thelike; and naturally-occurring substances such as shellac and the like.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose and the like; and acrylic acid polymerssuch as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)],ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE(trade name)] and the like.

Two or more kinds of the above-mentioned coating bases may be used in amixture at an appropriate ratio. In addition, for example, lightshielding agents such as titanium oxide, red ferric oxide and the likemay also be used during coating.

Since the compound of the present invention shows low toxicity (e.g.,acute toxicity, chronic toxicity, genetic toxicity, reproductivetoxicity, cardiotoxicity, carcinogenicity) and less side effects, it canbe used as a prophylactic or therapeutic agent, or diagnostic agent forvarious diseases in mammals (e.g., human, bovine, horse, dog, cat,monkey, mouse, rat).

The compound of the present invention has an excellent an orexin type 2receptor agonist activity, and may treat, prevent or ameliorate the riskof various neurological and psychiatric diseases associated with anorexin type 2 receptor. The compound of the present invention is usefulas an agent for the prophylaxis or treatment of various diseases such asnarcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome,narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomniasyndrome accompanied by daytime hypersomnia (e.g., Kleine Levinsyndrome, major depression with hypersomnia, Lewy body dementia,Parkinson's disease, progressive supranuclear paralysis, Prader-Willisyndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pickdisease type C, brain contusion, cerebral infarction, brain tumor,muscular dystrophy, multiple sclerosis, acute disseminatedencephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis,Wernicke's encephalitis, limbic encephalitis, Hashimoto'sencephalopathy), coma, loss of consciousness, obesity (e.g., malignantmastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmicobesity, hypop hyseal adiposity, hypoplasmic obesity, hypothyroidobesity, hypothalamic obesity, symptomatic obesity, infantile obesity,upper body obesity, alimentary obesity, hypogonadal obesity, systemicmastocytosis, simple obesity, central obesity), insulin resistancesyndrome, Alzheimer's disease, disturbance of consciousness such as comaand the like, side effects and complications due to anesthesia, sleepdisturbance, sleep problem, insomnia, Intermittent sleep, nocturnalmyoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleepdisorder of alternating worker, sleep disorder, night terror,depression, major depression, sleepwalking disease, enuresis, sleepdisorder, Alzheimer's dusk, diseases associated with circadian rhythm,fibromyalgia, condition arising from decline in the quality of sleep,overeating, obsessive compulsive eating disorder, obesity-relateddisease, hypertension, diabetes, elevated plasma insulin concentrationand insulin resistance, hyperlipidemia, hyperlipemia, endometrialcancer, breast cancer, prostate cancer, colorectal cancer, cancer,osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones,cardiac disease, abnormal heartbeat, arrhythmia, myocardial infarction,congestive cardiac failure, cardiac failure, coronary heart disease,cardiovascular disorder, sudden death, polycysticovarian disease,craniopharingioma, Froelich's syndrome, growth hormone deficient, normalmutant short stature, Turner's syndrome, children suffering from acutelymphoblastic leukemia, syndrome X, reproductive hormone abnormality,declining fertility, infertility, male gonadal function decline, sexualand reproductive dysfunction such as female male hirsutism, fetaldefects associated with pregnant women obesity, gastrointestinalmotility disorders such as obesity-related gastroesophageal reflux,obesity hypoventilation syndrome (Pickwick syndrome), respiratorydiseases such as dyspnea, inflammation such as systemic inflammation ofthe vascular system, arteriosclerosis, hypercholesterolemia,hyperuricemia, lower back pain, gall bladder disease, gout, kidneycancer, risk of secondary outcomes of obesity such as lowering the riskof left ventricular hypertrophy, migraine pain, headache, neuropathicpain, Parkinson's disease, psychosis, schizophrenia, facial flushing,night sweats, diseases of the genital/urinary system, diseases relatedto sexual function or fertility, dysthymic disorder, bipolar disorder,bipolar I disorder, bipolar II disorder, cyclothymic disorder, acutestress disorder, agoraphobia, generalized anxiety disorder, obsessivedisorder, panic attack, panic disorder, posttraumatic stress disorder,separation anxiety disorder, social phobia, anxiety disorder, acuteneurologial and psychiatric disorders such as cardiac bypass surgery andpost-transplant cerebral deficit, stroke, ischemic stroke, cerebralischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiacarrest, hypoglycemic nerve injury, Huntington's chorea, amyotrophiclateral sclerosis, multiple sclerosis, eye damage, retinopathy,cognitive impairment, muscle spasm, tremor, epilepsy, disordersassociated with muscle spasticity, delirium, amnestic disorder,age-related cognitive decline, schizoaffective disorder, delusionaldisorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue,medication-induced Parkinsonism syndrome, Jill-do La Tourette'ssyndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia,dyskinesia, attention deficit hyperactivity disorder (ADHD), behaviordisorder, urinary incontinence, withdrawal symptoms, trigeminalneuralgia, hearing loss, tinnitus, nerve damage, retinopathy, maculardegeneration, vomiting, cerebral edema, pain, bone pain, arthralgia,toothache, cataplexy, and traumatic brain injury (TBI).

Particularly, the compound of the present invention is useful as anagent for the prophylaxis or treatment of narcolepsy, idiopathichypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndromeaccompanied by narcolepsy-like symptoms, hypersomnia syndromeaccompanied by daytime hypersomnia (e.g., Parkinson's disease,Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer's disease,obesity, insulin resistance syndrome, cardiac failure, diseases relatedto bone loss, sepsis, disturbance of consciousness such as coma and thelike, side effects and complications due to anesthesia, and the like, oranesthetic antagonist.

While the dose of the compound of the present invention varies dependingon the subject of administration, administration route, target disease,symptom and the like, for example, when the compound of the presentinvention is administered orally or parenterally to an adult patient,its dose is for example, about 0.01 to 100 mg/kg body weight per dose,preferably 0.1 to 50 mg/kg body weight per dose and more preferably 0.5to 20 mg/kg body weight per dose. This amount is desirably administeredin one to 3 portions daily.

The compound of the present invention can be used in combination withother drugs (hereinafter to be abbreviated as concomitant drug).

By combining the compound of the present invention and a concomitantdrug, a superior effect, for example,

(1) the dose can be reduced as compared to single administration of thecompound of the present invention or a concomitant drug,(2) the drug to be combined with the compound of the present inventioncan be selected according to the condition of patients (mild case,severe case and the like),(3) the period of treatment can be set longer by selecting a concomitantdrug having different action and mechanism from the compound of thepresent invention,(4) a sustained treatment effect can be designed by selecting aconcomitant drug having different action and mechanism from the compoundof the present invention,(5) a synergistic effect can be afforded by a combined use of thecompound of the present invention and a concomitant drug, and the like,can be achieved.

In the present specification, the compound of the present invention anda concomitant drug used in combination are referred to as the“combination agent of the present invention”.

When using the combination agent of the present invention, theadministration time of the compound of the present invention and theconcomitant drug is not restricted, and the compound of the presentinvention or a pharmaceutical composition thereof, or the concomitantdrug or a pharmaceutical composition thereof can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration mode of the combination agent of the presentinvention and the concomitant drug is not particularly limited, and thecompound of the present invention and the concomitant drug only need tobe combined on administration. Examples of such administration modeinclude the following: (1) administration of a single preparationobtained by simultaneously processing the compound of the presentinvention and the concomitant drug, (2) simultaneous administration oftwo kinds of preparations of the compound of the present invention andthe concomitant drug, which have been separately produced, by the sameadministration route, (3) administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route in astaggered manner, (4) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by differentadministration routes, (5) administration of two kinds of preparationsof the compound of the present invention and the concomitant drug, whichhave been separately produced, by different administration routes in astaggered manner (e.g., administration in the order of the compound ofthe present invention and the concomitant drug, or in the reverse order)and the like.

The dose of the concomitant drug can be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug can beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.

For example, the content of the compound of the present invention in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 0.01 to about 100 wt %,preferably from about 0.1 to about 50 wt %, further preferably fromabout 0.5 to about 20 wt %, based on the whole preparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the whole preparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to about 99.99 wt %,preferably from about 10 to about 90 wt %, based on the preparation.

Similar contents may be employed even when the compound of the presentinvention and a concomitant drug are separately formulated intopreparations.

Examples of the concomitant drug include the followings. A therapeuticdrug for narcolepsy (e.g., methylphenidate, amphetamine, pemoline,phenelzine, protriptyline, sodium oxybate, modafinil, caffeine),antiobesity drug (amphetamine, benzfetamine, bromocriptine, bupropion,diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide,mazindol, methamphetamine, octreotide, octreotide, orlistat,phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa(registered trade mark), phenylpropanolamine, pramlintide,propylhexedrine, recombinant leptin, sibutramine, topiramate,zimelidine, zonisamide, Lorcaserin, metformin), acetylcholine esteraseinhibitor (e.g., donepezil, rivastigmine, galanthamine, zanapezil,idebenone, tacrine), antidementia agent (e.g., memantine), inhibitor ofβ amyloid protein production, secretion, accumulation, aggregationand/or deposition, β secretase inhibitor (e.g.,6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin,6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin,2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,an optically active form thereof, a salt thereof and a hydrate thereof,OM99-2 (WO01/00663)), γ secretase inhibitor, β amyloid proteinaggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368(National Publication of International Patent Application No.11-514333), PPI-558 (National Publication of International PatentApplication No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1),283-289)), β amyloid vaccine, β amyloid-degrading enzyme and the like,brain function enhancer (e.g., aniracetam, nicergoline), therapeuticdrug for Parkinson's disease [(e.g., dopamine receptor agonist (e.g.,L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline,amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl,selegiline, remacemide, riluzole), anticholinergic agent (e.g.,trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)],therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc.,neurotrophic factor), therapeutic drug for abnormal behavioraccompanying progress of dementia, wandering and the like (e.g.,sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189,IDN-6556, CEP-1347), neuronal differentiation • regenerate promoter(e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853,prosaptide,5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline,6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindoleand an optically active form, salt or hydrate thereof), non-steroidalantiinflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid drug(dexamethasop, hexestrol, cortisone acetate etc.), disease-modifyinganti-rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor,MAP kinase inhibitor), therapeutic agent for incontinence, frequenturination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride), phosphodiesterase inhibitor (e.g.,sildenafil(citrate)), dopamine agonist (e.g., apomorphine),antiarrhythmic drugs (e.g., mexiletine), sex hormone or a derivativethereof (e.g., progesterone, estradiol, estradiol benzoate), therapeuticagent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin,calcitonin salmon, estriol, ipriflavone, pamidronate disodium,alendronate sodium hydrate, incadronate disodium), parathyroid hormone(PTH), calcium receptor antagonists, therapeutic drug for insomnia(e.g., benzodiazepines medicament, non-benzodiazepines medicament,melatonin agonist, orexin receptor antagonists), therapeutic drug forschizophrenia (e.g., typical antipsychotic agents such as haloperidoland the like; atypical antipsychotic agents such as clozapine,olanzapine, risperidone, aripiprazole and the like; medicament acting onmetabotropic glutamate receptor or ion channel conjugated-type glutamatereceptor; phosphodiesterase inhibitor), benzodiazepines medicament(chlordiazepoxide, diazepam, potassium clorazepate, lorazepam,clonazepam, alprazolam etc.), L-type calcium channel inhibitor(pregabalin etc.), tricyclic or tetracyclic antidepressant (imipraminehydrochloride, amitriptyline hydrochloride, desipramine hydrochloride,clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor(fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide,sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalateetc.), serotonin-noradrenaline reuptake inhibitor (venlafaxinehydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochlorideetc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.),mirtazapine, trazodone hydrochloride, nefazodone hydrochloride,bupropion hydrochloride, setiptiline maleate, 5-HT_(1A) agonist,(buspirone hydrochloride, tandospirone citrate, osemozotan hydrochlorideetc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverse agonist, 5-HT₃ antagonist(cyamemazine etc.), heart non-selective β inhibitor (propranololhydrochloride, oxprenolol hydrochloride etc.), histamine Hi antagonist(hydroxyzine hydrochloride etc.), CRF antagonist, other antianxiety drug(meprobamate etc.), tachykinin antagonist (MK-869, saredutant etc.),medicament that acts on metabotropic glutamate receptor, CCK antagonist,β3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor(tiagabine hydrochloride etc.), N-type calcium channel inhibitor,carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDAantagonist (memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid antagonist, opioidagonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3,T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcyprominesulfate, moclobemide etc.), therapeutic drug for bipolar disorder(lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamateetc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor,sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride,methamphetamine hydrochloride etc.), therapeutic drug for alcoholism,therapeutic drug for autism, therapeutic drug for chronic fatiguesyndrome, therapeutic drug for spasm, therapeutic drug for fibromyalgiasyndrome, therapeutic drug for headache, therapeutic drug for quittingsmoking, therapeutic drug for myasthenia gravis, therapeutic drug forcerebral infarction, therapeutic drug for mania, therapeutic drug forhypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia,therapeutic drug for autonomic ataxia, therapeutic drug for male andfemale sexual dysfunction, therapeutic drug for migraine, therapeuticdrug for pathological gambler, therapeutic drug for restless legssyndrome, therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for lipid abnormality such as cholesterol-lowering drug(statin series (pravastatin sodium, atorvastatin, simvastatin,rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetaseinhibitor), therapeutic drug for abnormal behavior or suppressant ofdromomania due to dementia (sedatives, 20 antianxiety drug etc.),therapeutic drug for diabetes, therapeutic agent for diabeticcomplications, therapeutic drug for hypertension, therapeutic drug forhypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent,antithrombotic agent, anti-cancer agent and the like.

Two or more kinds of the above-mentioned concomitant drug may be used ina mixture at an appropriate ratio.

When the compound of the present invention is applied to each of theabove-mentioned diseases, it can also be used in combination withbiologics (e.g., antibody drug, nucleic acid or nucleic acid derivative,aptamer drug, vaccine preparation), or can be used in combination with agene therapy method and the like, or can also be used in combinationwith a treatment in psychiatric field without using drugs.

Examples of the antibody drug and vaccine preparation include vaccinepreparation against angiotensin II, vaccine preparation against CETP,CETP antibody, antibody against TNFα antibody and other cytokines,amyloid β vaccine preparation, vaccine for type 1 diabetes (e.g.,DIAPEP-277 of Peptor), anti-HIV antibody and HIV vaccine preparation, aswell as antibodies or vaccine preparations against cytokines,renin-angiotensin type enzymes and products thereof, antibodies orvaccine preparations against enzymes or proteins involved in blood lipidmetabolism, antibodies or vaccines relating to enzymes and proteinsinvolved in blood coagulation or fibrinolysis system, antibodies orvaccine preparations against proteins involved in sugar metabolism andinsulin resistance, and the like. In addition, it can be used incombination with biologics relating to growth factors such as GH, IGFand the like.

Examples of the gene therapy method include a treatment method usinggene relating to cytokine, renin-angiotensin type enzyme and productthereof, G protein, G protein conjugated receptor and phosphorylatingenzyme thereof, a treatment method using a DNA decoy such as NFκB decoyand the like, a treatment method using antisense, a treatment methodusing a gene relating to an enzyme or protein involved in blood lipidmetabolism (e.g., a gene relating to metabolism, excretion andabsorption of cholesterol or triglyceride or HDL-cholesterol or bloodphospholipid), a treatment method using a gene relating to an enzyme orprotein involved in angiogenesis therapy for peripheral vascularobstruction and the like (e.g., growth factors such as HGF, VEGF etc.),a treatment method using a gene relating to a protein involved inglucose metabolism and insulin resistance, antisense against cytokinessuch as TNF etc., and the like.

Examples of the treatment method in the psychiatric field without usingdrug include modified electroconvulsive therapy, deep brain stimulationtherapy, repetitive transcranial magnetic stimulation therapy,psychotherapy including cognitive behavioral therapy and the like.

The compound of the present invention can also be used in combinationwith various organ regeneration methods such as cardiac regeneration,renal regeneration, pancreatic regeneration, revascularization and thelike, cell transplantation therapy utilizing bone marrow cells (bonemarrow-derived mononuclear cell, myelogenic stem cell), or artificialorgan utilizing tissue engineering (e.g., artificial blood vessel,cardiomyocyte sheet).

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and theexamples can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

The elution by column chromatography in the Examples was performed underthe observation by TLC (Thin Layer Chromatography) unless otherwisespecified. In the observation by TLC, 60 F₂₅₄ manufactured by Merck wasused as a TLC plate, the solvent used as an elution solvent in columnchromatography was used as an eluent, and U detector was used for thedetection. In silica gel column chromatography, the indication of NHmeans use of aminopropylsilane-bonded silica gel and the indication ofDiol means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silicagel. In preparative HPLC (high performance liquid chromatography), theindication of C18 means use of octadecyl-bonded silica gel. The ratiofor elution solvent is, unless otherwise specified, a volume mixingratio.

¹H NMR was measured by Fourier transform NMR. For the analysis of 1HNMR, ACD/SpecManager (trade name) software and the like were used. Peaksof a hydroxy group, an amino group and the like, having very mild protonpeak, are not sometimes described.

MS was measured by LC/MS. As the ionization method, ESI method, or APCImethod was used. The data indicates actual measured value (found). Whilemolecular ion peak is generally observed, a fragment ion is sometimesobserved. In the case of a salt, a molecular ion peak or fragment ionpeak of free form is generally observed.

The unit of sample concentration (c) for optical rotation ([α]_(D)) isg/100 mL.

Elemental analysis value (Anal.) is described as calculated value(Calcd) and actual measured value (Found).

In Example, the cis/trans expression contained in compound namebasically means a cis or trans mixture of two kinds of optical isomerswhen the corresponding partial structure contains two asymmetriccenters. Exceptionally, the cis/trans expression means a single opticalisomer when indicated as “optical isomer”.

Peaks by powder X-ray diffraction in the Examples mean peaks measured atroom temperature by using Ultima IV (Rigaku Corporation, Japan) using CuKα radiation as a radiation source. The measurement conditions are asfollows.

Electric pressure/Electric current: 40 kV/50 mA

Scan speed: 6 degrees/min

Scan range of 2 Theta: 2-35 degrees

The crystallinity by powder X-ray diffraction in the Examples wascalculated by the Hermans method.

In the following Examples, the following abbreviations are used.

mp: melting pointMS: mass spectrumM: mol concentrationN: normalityCDCl₃: deuterochloroformDMSO-d₆: deuterodimethyl sulfoxide¹H NMR: proton nuclear magnetic resonanceLC/MS: liquid chromatograph mass spectrometerESI: electrospray ionizationAPCI: atmospheric pressure chemical ionizationPd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)DIAD: diisopropyl (E)-diazene-1,2-dicarboxylateHATU:(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminiumhexafluorophosphatePPh₃: triphenylphosphineTFA: trifluoroacetic acidDMAP: N,N-dimethyl-4-aminopyridineWSC: N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimideDIPEA: N-ethyl-N-isopropylpropan-2-aminen-BuLi: n-butyllithium

DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide

THF: tetrahydrofuranDME: 1,2-dimethoxyethaneWSC-HCl: N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride(1:1)EtOH: ethanolBoc₂O: di-tert-butyl dicarbonateDMSO: (methylsulfinyl)methaneAcOH: acetic acidTEA: triethylamine

Example 1 methylcis-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylateA) (cis-4-(allyloxy)cyclohexyl)benzene

To a mixture of cis-4-phenylcyclohexanol (20.0 g) and THF (300 ml) wasadded 60% sodium hydride (5.90 g) at 0° C. The mixture was stirred undernitrogen atmosphere, at 0° C. for 30 min, and allyl bromide (20.6 g) wasadded thereto. The mixture was stirred under nitrogen atmosphere, at 60°C. for 12 hr. The mixture was poured into water, and extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (22.0 g).

1H NMR (400 MHz, CDCl₃) δ 1.51-1.71 (4H, m), 1.84-1.96 (2H, m),2.05-2.11 (2H, m), 2.53-2.61 (1H, m), 3.69-3.73 (1H, m), 4.02-4.05 (2H,m), 5.21 (1H, dd, J=10.4, 1.6 Hz), 5.21 (1H, dd, J=16.8, 1.6 Hz),5.96-6.05 (1H, m), 7.20-7.35 (5H, m).

B) ((cis-4-phenylcyclohexyl)oxy)acetaldehyde

To a mixture of (cis-4-(allyloxy)cyclohexyl)benzene (11.0 g), THF (220ml) and water (110 ml) was added potassium osmate(VI) dihydrate (937mg). The mixture was stirred at 15° C. for 1 hr, and sodium periodate(32.6 g) was added thereto. The mixture was stirred at 15° C. for 12 hr.The same reaction was carried out twice, and the reaction solutions werecombined. The mixture was poured into water, and extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (16.5 g).

¹H NMR (400 MHz, CDCl₃) δ 1.60-1.75 (4H, m), 1.84-1.96 (2H, m),2.05-2.13 (2H, m), 2.51-2.64 (1H, m), 3.72-3.75 (1H, m), 4.11 (2H, s),7.20-7.35 (5H, m), 9.84 (1H, s).

C) 2-amino-3-((cis-4-phenylcyclohexyl)oxy)propanenitrile

To a mixture of ((cis-4-phenylcyclohexyl)oxy)acetaldehyde (16.5 g) andEtOH (400 ml) was added ammonium acetate (58.3 g). The mixture wasstirred under nitrogen atmosphere, at 15° C. for 15 min, andtrimethylsilylcyanide (15.0 g) was added thereto. The mixture wasstirred at 15° C. for 12 hr, and left stand for 12 hr, and then stirredfor 12 hr. The mixture was poured into water, and extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (11.0 g).

¹H NMR (400 MHz, CDCl₃) δ 1.55-1.71 (4H, m), 1.83-1.94 (4H, m),2.07-2.12 (2H, m), 2.53-2.61 (1H, m), 3.62-3.70 (2H, m), 3.71-3.77 (1H,m), 3.91 (1H, t, J=4.4 Hz), 7.17-7.34 (5H, m).

D) N-(tert-butoxycarbonyl)-O-(cis-4-phenylcyclohexyl)serine

A mixture of 2-amino-3-((cis-4-phenylcyclohexyl)oxy)propanenitrile (11.0g) and conc. hydrochloric acid (45 ml) was stirred at 100° C. for 12 hr.The mixture was allowed to be cooled to temperature, to the reactionmixture was added 1,4-dioxane (50 ml), and the pH of the mixture wasadjusted to 10 with 12M aqueous sodium hydroxide solution. To themixture was added Boc₂O (11.8 g), and the mixture was stirred at 15° C.for 3 hr. To the mixture was added water, and the mixture was washedwith petroleum ether. The pH of the mixture was adjusted to 6 with 1Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive the title compound (13.0 g).

MS 386.2 [M+Na]⁺.

E) tert-butyl3-hydroxy-5-oxo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

To a mixture of N-(tert-butoxycarbonyl)-O-(cis-4-phenylcyclohexyl)serine(2.60 g), Meldrum's acid (1.13 g), DMAP (1.31 g) and dichloromethane (26ml) was added dropwise a solution of N,N′-dicyclohexylcarbodiimide (1.77g) in dichloromethane (10 ml) at 0° C. The mixture was stirred undernitrogen atmosphere, at 15° C. for 12 hr. The mixture was cooled to 0°C., ethyl acetate was added thereto, and the insoluble substance wasfiltered off. The filtrate was washed with 10% aqueous citric acidsolution, water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. To the obtainedresidue was added ethyl acetate (30 ml), and the mixture was stirred at77° C. for 30 min. The mixture was allowed to be cooled to roomtemperature, and concentrated under reduced pressure to give the titlecompound (2.51 g).

MS 287.9 [M+H-Boc]⁺.

F) tert-butylcis-3-hydroxy-5-oxo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl3-hydroxy-5-oxo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(2.51 g) and dichloromethane (50 ml) were added AcOH (6.22 g) and sodiumborohydride (980 mg) at −15° C. The mixture was stirred under nitrogenatmosphere, at −5° C. for 5 hr. To the mixture was added saturatedaqueous ammonium chloride solution at 0° C., and the mixture wasextracted with dichloromethane. The organic layer was separated, washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (1.60 g).

MS 412.1 [M+Na]⁺.

G) tert-butylcis-3-hydroxy-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butylcis-3-hydroxy-5-oxo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(1.60 g) and THF (40 ml) was added 10M dimethyl sulfide borane (1.23ml). The mixture was stirred under nitrogen atmosphere, at 66° C. for 1hr. The mixture was cooled to 0° C., ethyl acetate was added thereto,and then saturated aqueous ammonium chloride solution was added thereto,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to give the title compound (1.40 g).

¹H NMR (400 MHz, CDCl₃) δ 1.44-1.57 (11H, m), 1.68-1.73 (4H, m),2.00-2.05 (4H, m), 2.49-2.54 (1H, m), 3.41-4.00 (7H, m), 4.48-4.54 (1H,m), 7.18-7.30 (5H, m).

H) tert-butyltrans-3-((4-nitrobenzoyl)oxy)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butylcis-3-hydroxy-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(1.20 g), 4-nitrobenzoic acid (587 mg) and THF (12 ml) were added PPh₃(1.26 g) and DIAD (969 mg). The mixture was stirred under nitrogenatmosphere, at 15° C. for 12 hr. The mixture was poured into water, andextracted with ethyl acetate. The organic layer was separated, washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (1.41 g).

MS 425.1 [M+H-Boc]⁺.

I) tert-butyltrans-3-hydroxy-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyltrans-3-((4-nitrobenzoyl)oxy)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(1.41 g) and methanol (14 ml) was added potassium carbonate (1.11 g).The mixture was stirred under nitrogen atmosphere, at 15° C. for 1.5 hr.The mixture was poured into water, and extracted with ethyl acetate. Theorganic layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (900 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.45-2.08 (19H, m), 2.21-2.24 (1H, m),2.50-2.55 (1H, m), 2.29-3.84 (6H, m), 4.44-4.46 (1H, m), 7.21-7.32 (5H,m).

J) tert-butyltrans-3-((methylsulfonyl)oxy)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyltrans-3-hydroxy-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(900 mg) and THF (15 ml) were added TEA (485 mg) and methanesulfonylchloride (412 mg). The mixture was stirred under nitrogen atmosphere, at15° C. for 1 hr. The mixture was poured into water, and extracted withethyl acetate. The organic layer was separated, washed with water, driedover anhydrous sodium sulfate, and concentrated under reduced pressureto give the title compound (1.13 g).

¹H NMR (400 MHz, CDCl₃) δ 1.45-1.73 (15H, m), 1.98-2.00 (2H, m),2.21-2.56 (3H, m), 3.07 (3H, s), 3.52-3.67 (5H, m), 4.03-4.15 (1H, m),4.26-4.29 (1H, m), 7.20-7.32 (5H, m).

K) tert-butylcis-3-azido-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyltrans-3-((methylsulfonyl)oxy)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(200 mg) and DMA (3 ml) was added sodium azide (287 mg), and the mixturewas subjected to microwave irradiation at 120° C. for 1 hr. The samereaction was carried out using tert-butyltrans-3-((methylsulfonyl)oxy)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(900 mg), DMA (10 ml) and sodium azide (1.29 g), and the two reactionmixtures are combined. The mixture was poured into water, and extractedwith ethyl acetate. The organic layer was separated, washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (834 mg).

MS 301.1 [M+H-Boc]⁺.

L) tert-butylcis-3-amino-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butylcis-3-azido-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(834 mg), THF (8 ml) and water (0.25 ml) was added PPh₃ (367 mg). Themixture was stirred under nitrogen atmosphere, at 50° C. for 16 hr, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl 20 acetate) to give the titlecompound (380 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.40-1.47 (9H, m), 1.57-1.78 (8H, m),1.97-2.06 (4H, m), 2.47-2.57 (1H, m), 3.26-3.93 (7H, m), 7.17-7.22 (3H,m), 7.26-7.32 (2H, m).

M) tert-butylcis-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butylcis-3-amino-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(380 mg), TEA (154 mg) and THF (4 ml) was added methanesulfonyl chloride(151 mg) at 0° C. The mixture was stirred under nitrogen atmosphere, at15° C. for 2 hr. The mixture was poured into water, and extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (360 mg).

MS 475.1 [M+Na]⁺.

N)N-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamidetrifluoroacetate

To a mixture of tert-butylcis-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate(180 mg) and dichloromethane (2.5 ml) was added TFA (0.5 ml) at 0° C.The mixture was stirred under nitrogen atmosphere, at 15° C. for 1.5 hr.The mixture was concentrated under reduced pressure to give the titlecompound (226 mg).

MS 353.1 [M+H]⁺.

O) methylcis-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture ofN-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamidetrifluoroacetate (226 mg) and dichloromethane (3 ml) were added TEA (147mg) and methyl chloroformate (69 mg) at 0° C. The mixture was stirredunder nitrogen atmosphere, at 15° C. for 1 hr. The mixture was pouredinto water, and extracted with dichloromethane. The organic layer wasseparated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by preparative HPLC, the MeCN was evaporated under reducedpressure, and the residue was freeze-dried to give the title compound(75 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.56-1.74 (6H, m), 1.98-2.03 (2H, m),2.10-2.18 (1H, m), 2.29-2.33 (1H, m), 3.51-3.56 (1H, m), 3.01 (3H, s),3.30-3.41 (1H, m), 3.50-3.94 (7H, m), 4.05-4.12 (2H, m), 5.38-5.54 (1H,m), 7.15-7.33 (5H, m)

Example 6N-(cis-1-(azetidin-1-ylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide

To a mixture ofN-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamidetrifluoroacetate (140 mg), DIPEA (223 mg) and dichloromethane (3 ml) wasadded bis(trichloromethyl) carbonate (45 mg) at 0° C. The reactionmixture was stirred at 0° C. for 30 min, and azetidine hydrochloride (31mg) was added thereto. The mixture was stirred under nitrogenatmosphere, at 25° C. for 12 hr. The mixture was poured into water, andextracted with ethyl acetate. The organic layer was separated, washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by HPLC(mobile phase: water/MeCN (containing 0.05% aqueous ammonia)). Theobtained fraction was concentrated under reduced pressure, and theresidue was freeze-dried to give the title compound (45 mg).

1H NMR (400 MHz, CDCl₃) δ 1.51-1.74 (6H, m), 1.99-2.06 (2H, m),2.12-2.32 (4H, m), 2.51-2.55 (1H, m), 3.00 (3H, s), 3.23-3.32 (1H, m),3.43-3.50 (1H, m), 3.64-3.74 (2H, m), 3.81-3.94 (3H, m), 4.03-4.11 (3H,m), 4.26-4.32 (1H, m), 5.77 (1H, d, J=8.0 Hz), 7.17-7.32 (5H, m).

Example 7N-(cis-1-(cyclobutylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide

To a mixture ofN-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamidetrifluoroacetate (140 mg) and dichloromethane (3 ml) were added TEA (121mg) and cyclobutanecarbonyl chloride (53 mg) at 0° C. The mixture wasstirred under nitrogen atmosphere, at 25° C. for 12 hr. The mixture waspoured into water, and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by HPLC (mobile phase: water/MeCN (containing 0.05% aqueousammonia)). The obtained fraction was concentrated under reducedpressure, and the residue was freeze-dried to give the title compound(46 mg).

1H NMR (400 MHz, CDCl₃) δ 1.45-1.51 (1H, m), 1.60-1.81 (5H, m),1.86-2.55 (11H, m), 2.99-3.03 (3H, m), 3.15-3.96 (6H, m), 4.03-4.35 (2H,m), 5.24-5.29 (1H, m), 7.18-7.21 (3H, m), 7.27-7.31 (2H, m).

Example 8cis-N,N-dimethyl-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide

To a mixture ofN-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamidetrifluoroacetate (140 mg), TEA (121 mg) and dichloromethane (3 ml) wasadded dimethylcarbamoyl chloride (48 mg) at 0° C. The mixture wasstirred under nitrogen atmosphere, at 25° C. for 12 hr. The mixture waspoured into water, and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by HPLC (mobile phase: water/MeCN (containing 0.05% aqueousammonia)). The obtained fraction was concentrated under reducedpressure, and the residue was freeze-dried to give the title compound(48 mg).

1H NMR (400 MHz, CDCl₃) δ 1.49-1.51 (2H, m), 1.65-1.73 (4H, m),1.97-2.15 (4H, m), 2.49-2.56 (1H, m), 2.85 (6H, s), 3.01 (3H, s),3.27-3.34 (1H, m), 3.61-3.75 (3H, m), 3.79-3.85 (1H, m), 4.11-4.16 (1H,m), 4.33-4.38 (1H, m), 6.23 (1H, d, J=6.4 Hz), 7.17-7.23 (3H, m),7.25-7.32 (2H, m).

The compounds of Examples are shown in the following tables. MS in thetables means actual measured value. The compounds of Examples 2 to 5 and9 to 11 in the following tables were produced according to the methodsdescribed in the above-mentioned Examples, or methods analogous thereto.

TABLE 1 EXAMPLE IUPAC NAME Structure ADDITIVE MS 1 methyl cis-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

409.1 2 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide

353.0 3 ethyl cis-3-((methylsulfonyl)amino)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl) pyrrolidine-1-carboxylate

425.0 4 N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-4-phenylcyclohexyl)oxy)methyl) pyrrolidin-3-yl)methanesulfonamide

421.1 5 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1-(3,3,3-trifluoropropanoyl)pyrrolidin- 3-yl)methanesulfonamide

461.2 6 N-(cis-1-(azetidine-1-carbonyl)-2- (((cis-4-phenylcyclohexyl)oxy)methyl) pyrrolidin-3-yl]methanesulfonamide

436.3 7 N-(cis-1-(cyclobutanecarbonyl)-2- (((cis-4-phenylcyclohexyl)oxy)methyl) pyrrolidin-3-yl)methanesulfonamide

435.3 8 cis-N,N,-dimethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) pyyrolidine-1-carboxamide

424.3 9 cis-3-((methanesulfonyl)amino)- N,N-dimethyl-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl) oxy)methyl)pyrrolidine-1-carboxamide

492.0 10 N-(cis-1-(2-hydroxy-2- methylpropanoyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) pyrrolidin-3-yl)methanesulfonamide

439.3 11 cis-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3- ((methanesulfonyl)amino)-N,N-dimethylpyrrolidine-1-carboxamide

445.1

Experimental Example 1: Obtainment of Cell Stably Expressing HumanOrexin Type 2 Receptor (hOX2R)

To obtain a cell clone stably expressing human orexin type 2 receptor,human orexin type 2 receptor cDNA was inserted into pcDNA3.1(+) plasmidvector (Invitrogen), and a plasmid DNA for expression of human orexintype 2 receptor (pcDNA3.1(+)/hOX2R) was cloned. The plasmid DNA wasintroduced into CHO-dhfr cell by an electroporation method, and humanorexin type 2 receptor expressing clone cells were obtained by limitingdilution method by using G418 drug resistance as a selection marker.

Experimental Example 2: Measurement of Orexin Type 2 Receptor AgonistActivity

CHO cells forcibly expressing human OX2 receptor were seeded in eachwell of 384 well black transparent bottom plate (BD Falcon) at 7,500cells/well, and cultured for one day in a 5% CO₂ incubator at 37° C.After removal of the medium in the cell plate, assay buffer A containinga calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES(Thermo Fisher Scientific), 0.1% BSA (Wako Pure Chemical Industries,Ltd. or Sigma-Aldrich), 2.5μg/mL Fluo-4 AM (DOJINDO Chemical), 0.08%Pluronic F127 (DOJINDO Chemical), 1.25 mM probenecid (DOJINDO Chemical))was added at 30 μL/well. The plate was stood for 30 min in a 5% CO₂incubator at 37° C., and further stood at room temperature for 30 min. Atest compound prepared by diluting with assay buffer B (HBSS, 20 mMHEPES, 0.1% BSA) was added at 10 μL/well, and the fluorescence value wasmeasured by FDSSpCELL (Hamamatsu Photonics K.K.) every one sec for 1min, and thereafter every two sec for 1 min 40 sec. The activity (%) ofthe test compound was calculated assuming that variation in thefluorescence value when DMSO was added instead of the test compound was0%, and variation in the fluorescence value when orexin A (human)(PEPTIDE INSTITUTE, INC.) was added at the final concentration of 10 nMwas 100%. The agonist activity EC₅₀ of each compound are shown in Table2. Unless otherwise specified, the maximum agonist activity of eachcompound was 90% or more, when the maximum agonist activity of orexin Awas considered as 100%. As is clear from the results, the compound ofthe present invention was shown to have an agonist activity on hOX2R.

TABLE 2 Example No. EC₅₀ (nM) 1 130 2 3600 3 240 4 47 5 760 6 17 7 40 813 9 270 10 410 11 82

Formulation Example 1 (production of capsule) 1) compound of Example 130 mg 2) crystalline cellulose 10 mg 3) lactose 19 mg 4) magnesiumstearate  1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (production of tablet) 1) compound of Example 1 30g 2) lactose 50 g 3) cornstarch 15 g 4) calcium carboxymethylcellulose44 g 5) magnesium stearate  1 g 1000 tablets 140 g in total

The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water,vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and1 g of 5), and the mixture is punched by a tableting machine. In thisway, 1000 tablets containing 30 mg of the compound of Example 1 pertablet are obtained.

INDUSTRIAL APPLICABILITY

The compound of the present invention has an orexin type 2 receptoragonist activity, and is useful as an agent for the prophylaxis ortreatment of narcolepsy.

This application is based on patent application No. 2017-150683 filed onAug. 3, 2017 in Japan, the contents of which are encompassed in fullherein.

1. A compound represented by the formula:

wherein R¹ is an acyl group or a hydrogen atom; R² is an optionallysubstituted 3- to 6-membered saturated cyclic group; R³ is an optionallysubstituted C₁₋₆ alkyl group, a mono- or di-C₁₋₆ alkylamino group or aC₃₋₆ cycloalkyl group; and Ring A is an azetidine ring or a pyrrolidinering, each optionally further substituted, or a salt thereof.
 2. Thecompound or salt according to claim 1, wherein R¹ is (1) a C₁₋₆alkoxy-carbonyl group, (2) a C₁₋₆ alkyl-carbonyl group optionallysubstituted by 1 to 3 substituents selected from a halogen atom and ahydroxy group, (3) a C₃₋₁₀ cycloalkyl-carbonyl group, (4) a mono- ordi-C₁₋₆ alkyl-carbamoyl group, (5) a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, or (6) a hydrogen atom; R² is (1) a C₃₋₆cycloalkyl group optionally substituted by C₆₋₁₄ aryl group(s)optionally substituted by 1 to 3 optionally halogenated C₁₋₆ alkylgroups, or (2) a 3- to 6-membered saturated monocyclic non-aromaticheterocyclic group optionally substituted by 5- to 14-membered aromaticheterocyclic group(s) optionally substituted by 1 to 3 halogen atoms; R³is a C₁₋₆ alkyl group; and Ring A is a pyrrolidine ring.
 3. The compoundor salt according to claim 1, wherein R¹ is (1) an azetidinylcarbonylgroup, (2) a cyclobutylcarbonyl group, (3) a mono- or di-C₁₋₆alkyl-carbamoyl group, or (4) a C₁₋₆ alkoxy-carbonyl group; R² is a C₃₋₆cycloalkyl group substituted by one C₆₋₁₄ aryl group; R³ is a C₁₋₆ alkylgroup; and Ring A is a pyrrolidine ring.
 4. The compound or saltaccording to claim 1, wherein R¹ is (1) an azetidinylcarbonyl group, (2)a cyclobutylcarbonyl group, or (3) a mono- or di-C₁₋₆ alkyl-carbamoylgroup; R² is a C₃₋₆ cycloalkyl group substituted by one C₆₋₁₄ arylgroup; R³ is a C₁₋₆ alkyl group; and Ring A is a pyrrolidine ring. 5.N-(cis-1-(Azetidin-1-ylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide,or a salt thereof. 6.N-(cis-1-(Cyclobutylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide,or a salt thereof. 7.cis-N,N-Dimethyl-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide,or a salt thereof.
 8. A medicament comprising the compound or saltaccording to claim
 1. 9.-11. (canceled)
 12. A method of activating anorexin type 2 receptor in a mammal, which comprises administering aneffective amount of the compound or salt according to claim 1 to themammal.
 13. A method for the prophylaxis or treatment of narcolepsy in amammal, which comprises administering an effective amount of thecompound or salt according to claim 1 to the mammal.
 14. (canceled)